Hemiplegic Migraines Exacerbated using an Injectable GLP-1 Agonist for Weight Loss.

The widespread adoption of Glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of obesity and diabetes has raised concerns about their potential adverse effects, including the induction of depression and suicide ideation. We report on a male patient in his early 50s with a complex medical history, including adult Attention-Deficit/Hyperactive Disorder, narcolepsy with cataplexy, and major depressive disorder in remission, who experienced exacerbated hemiplegic migraines after initiating treatment with an injectable GLP-1 agonist (Saxenda) for weight loss. Despite a previous history of experiencing hemiplegic migraines once or twice a year, the patient reported daily occurrences of migraines, many of which were hemiplegic, during the 60 days of GLP-1 agonist treatment. The migraines abated only upon discontinuation of the medication. This case underscores the need to carefully consider patient history and potential genetic predispositions when prescribing GLP-1 agonists, highlighting the complex interactions between these medications, existing comorbidities, and the dopaminergic and calcitonin gene-related peptide pathways. Our findings suggest that GLP-1 agonists, while beneficial for some, may pose significant risks for patients with specific genetic backgrounds or neurological conditions, calling for personalized approaches to treatment and increased awareness of potential adverse effects.

A historical perspective on clonidine as an alpha-2A receptor agonist in the treatment of addictive behaviors: Focus on opioid dependence.

Clonidine operates through agonism at the alpha-2A receptor, a specific subtype of the alpha-2-adrenergic receptor located predominantly in the prefrontal cortex. By inhibiting the release of norepinephrine, which is responsible for withdrawal symptoms, clonidine effectively addresses withdrawal-related conditions such as anxiety, hypertension, and tachycardia. The groundbreaking work by Gold et al. demonstrated clonidine's ability to counteract the effects of locus coeruleus stimulation, reshaping the understanding of opioid withdrawal within the field. In the 1980s, the efficacy of clonidine in facilitating the transition to long-acting injectable naltrexone was confirmed for individuals motivated to overcome opioid use disorders (OUDs), including physicians and executives. Despite challenges with compliance, naltrexone offers sustained blockade of opioid receptors, reducing the risk of overdose, intoxication, and relapse in motivated patients in recovery. The development of clonidine and naltrexone as treatment modalities for OUDs, and potentially other addictions, including behavioral ones, underscores the potential for translating neurobiological advancements from preclinical models (bench) to clinical practice (bedside), ushering in innovative approaches to addiction treatment.

The Effects of Chronic Psychostimulant Administration on Bone Health: A Review.

(1) Background: Methylphenidate (MP) and amphetamine (AMP) are psychostimulants that are widely prescribed to treat Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy. In recent years, 6.1 million children received an ADHD diagnosis, and nearly 2/3 of these children were prescribed psychostimulants for treatment. The purpose of this review is to summarize the current literature on psychostimulant use and the resulting effects on bone homeostasis, biomechanical properties, and functional integrity. (2) Methods: Literature searches were conducted from Medline/PubMed electronic databases utilizing the search terms "methylphenidate" OR "amphetamine" OR "methylphenidate" AND "bone health" AND "bone remodeling" AND "osteoclast" AND "osteoblast" AND "dopamine" from 01/1985 to 04/2023. (3) Results: Of the 550 publications found, 44 met the inclusion criteria. Data from identified studies demonstrate that the use of MP and AMP results in decreases in specific bone properties and biomechanical integrity via downstream effects on osteoblasts and osteoclast-related genes. (4) Conclusions: The chronic use of psychostimulants negatively affects bone integrity and strength as a result of increased osteoclast activity. These data support the need to take this into consideration when planning the treatment type and duration for bone fractures.

Dopamine Dysregulation in Reward and Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is primarily characterized by core deficits in social skills, communication, and cognition and by repetitive stereotyped behaviors. These manifestations are variable between individuals, and ASD pathogenesis is complex, with over a thousand implicated genes, many epigenetic factors, and multiple environmental influences. The mesolimbic dopamine (DA) mediated brain reward system is held to play a key role, but the rapidly expanding literature reveals intricate, nuanced signaling involving a wide array of mesolimbic loci, neurotransmitters and receptor subtypes, and neuronal variants. How altered DA signaling may constitute a downstream convergence of the manifold causal origins of ASD is not well understood. A clear working framework of ASD pathogenesis may help delineate common stages and potential diagnostic and interventional opportunities. Hence, we summarize the known natural history of ASD in the context of emerging data and perspectives to update ASD reward signaling. Then, against this backdrop, we proffer a provisional framework that organizes ASD pathogenesis into successive levels, including (1) genetic and epigenetic changes, (2) disrupted mesolimbic reward signaling pathways, (3) dysregulated neurotransmitter/DA signaling, and finally, (4) altered neurocognitive and social behavior and possible antagonist/agonist based ASD interventions. This subdivision of ASD into a logical progression of potentially addressable parts may help facilitate the rational formulation of diagnostics and targeted treatments.

Prenatal tobacco and tobacco-cannabis co-exposure: Relationship with attention and memory in middle childhood.

We examined associations between prenatal tobacco exposure (with and without cannabis exposure) and children's performance on laboratory measures of sustained attention, attentional set shifting, and working memory in middle childhood (9-12 years of child age). Participants were recruited in the first trimester of pregnancy and oversampled for prenatal tobacco exposure; with a smaller sample (n = 133; n = 34 non-substance exposed, n = 37 exposed to tobacco only, n = 62 co-exposed) invited (oversampled for co-exposure) to participate in the middle-childhood assessment (M age = 10.6, SD = 0.77; 68% Black, 20% Hispanic). Results for sustained attention indicated lower attention (percent hits) at the first epoch for tobacco only exposed compared to non-exposed and co-exposed; a trend (p = .07) towards increases in impulsive responding across time (a total of 8 epochs) for tobacco exposed (with and without cannabis) compared to non-exposed children; and a significant association between higher number of cigarettes in the first trimester and greater increases in impulsive responding across epochs. However, children prenatally exposed to tobacco (with and without cannabis) demonstrated greater short-term memory compared to children not prenatally exposed, and this difference was driven by higher scores for children prenatally co-exposed to tobacco and cannabis compared to those who were non-exposed. Overall, results suggest that prenatal tobacco exposure, especially in the first trimester, may increase risk for impulsive responding on tasks requiring sustained attention, and that co-use of cannabis did not exacerbate these associations. The higher short-term memory scores among children who were co-exposed compared to non-exposed are perplexing and need replication, particularly in studies with larger sample sizes and samples exposed only to cannabis to examine this more closely.

The Effects of Nicotine and Cannabinoids on Cytokines.

BACKGROUND: The usage of nicotine and cannabinoids has rapidly grown in popularity, leading to increased research into how they can affect people's health, both positively and negatively. Nicotine, Cannabidiol (CBD), and Tetrahydrocannabidiol (THC) have been shown to have significant effects on cytokine function and inflammatory response. OBJECTIVE: This study aimed to review and summarize the current literature on the effects of nicotine and cannabinoids on cytokines, including interleukins, TNF, IFN, and TGF-ß. METHODS: Literature search was conducted on Medline/PubMed electronic databases utilizing the search terms "nicotine" OR "cannabis" OR "cannabinoids" AND "cytokine" AND "inflammation" AND "stress" AND "immune" from 11/1973 to 02/2024. RESULTS: THC and CBD usage have been associated with conflicting impacts on immune response, and observed to both exacerbate and inhibit inflammation. Nicotine has been shown to be generally proinflammatory with regards to cytokines. These responses have been reported to have significant effects on bodily response to inflammation-related diseases. Nicotine usage is associated with worsened outcomes for some conditions, like chronic pain, but improved outcomes for others, like arthritis. The impacts of cannabinoid usage tend to be more positive, exerting anti-inflammatory effects across a wide range of diseases. Given the widespread usage of these substances, it is important to understand the nature of their consequences on immune functions and the underlying mechanisms by which they act. CONCLUSION: This review has covered how cannabinoids and nicotine affect inflammation directly and how these effects can be attributed to the treatment of inflammatory diseases. In summary, the existing research studying the effects of cannabinoids and nicotine supports the major relationship between nicotine and cannabis use and inflammatory diseases.

Potential Link Between Exercise and N-Methyl-D-Aspartate Glutamate Receptors in Alcohol Use Disorder: Implications for Therapeutic Strategies.

Alcohol use disorder (AUD) is a significant risk factor, accounting for approximately 13% of all deaths in the US. AUD not only destroys families but also causes economic losses due to reduced productivity, absenteeism, and healthcare expenses. Statistics revealing the sustained number of individuals affected by AUD over the years underscore the need for further understanding of the underlying pathophysiology to advance novel therapeutic strategies. Previous research has implicated the limbic brain regions N-methyl-D-aspartate glutamate receptors (NMDAR) in the emotional and behavioral effects of AUD. Given that aerobic exercise can modulate NMDAR activity and sensitivity to alcohol, this review presents a summary of clinical and basic science studies on NMDAR levels induced by alcohol consumption, as well as acute and protracted withdrawal, highlighting the potential role of aerobic exercise as an adjunctive therapy for AUD. Based on our findings, the utility of exercise in the modulation of reward-linked receptors and AUD may be mediated by its effects on NMDA signaling. These data support further consideration of the potential of aerobic exercise as a promising adjunctive therapy for AUD.

Vaporized Δ9-tetrahydrocannabinol exposure in utero has negative effects on attention in a dose- and sex-dependent manner.

There has been an increasing use of cannabis during pregnancy in recent years. Studies have indicated that THC exposure in utero may increase the risk of attention deficits and memory impairments in adolescence. The goal of the present study is to investigate the effects of vaporized THC exposure during pregnancy on offspring memory and attention performance in early and late adolescence. Pregnant dams were exposed to vaporized THC (10 mg or 40 mg) daily from gestational day 2 until labor. Pups were given either a standard or a high-fat diet at weaning and tested in early and late adolescence in two memory tests, the Novel Object Recognition (NOR) test and the Morris Water Maze (MWM) test, and a test of attention, the Object-Based Attention (OBA) test. Rats exposed to low-dose THC showed significantly decreased object exploration in both the NOR and OBA tests, indicating decreased attention. Object exploration time in OBA was significantly lower in females than males. Additionally, post hoc analysis of MWM tests showed some differences in learning patterns for HD THC offspring in early adolescence, possibly due to diet interaction, but ultimate performance was not impacted. While there are existing studies examining prenatal exposure to THC in rodents, this is the first to our knowledge examining memory and attention in adolescence following vaporized THC exposure in utero, and we find indications that prenatal THC exposure may lead to attention deficits and altered memory performance.

The role of fatty acid-binding protein 5 and 7 on locomotor, anxiety and social behavior: Interaction with NMDA signaling.

The endocannabinoid system has been shown to be a powerful mediator of anxiety, learning and memory, as well as nociception behaviors. Exogenous cannabinoids like delta-9-tetrahydrocannabinol mimic the naturally occurring endogenous cannabinoids found in the mammalian central and peripheral nervous system. The hydrophobic properties of endocannabinoids mean that these psychoactive compounds require help with cellular transport. A family of lipid intracellular carriers called fatty acid-binding proteins (FABPs) can bind to endocannabinoids. Pharmacological inhibition or genetic deletion of FABP subtypes 5 and 7 elevates whole-brain anandamide (AEA) levels, a type of endocannabinoid. This study examined locomotor behavior, anxiety-like behavior, and social behavior in FABP5-/- and FABP7-/- mice. Furthermore, we measured N-methyl-D-aspartate (NMDA) receptor levels in the brain to help identify potential underlying mechanisms related to the behavioral findings. Results showed that both male and female FABP5-/- mice exhibited significantly lower activity when compared with both FABP5/7+/+ (control) and FABP7-/-. For social behavior, male, but not female, FABP5-/- mice spent more time interacting with novel mice compared with controls (FABP5/7+/+) and FABP7-/- mice. No significant difference was found for anxiety-like behavior. Results from the NMDA autoradiography revealed [3H] MK-801 binding to be significantly increased within sub-regions of the striatum in FABP7-/- compared with control. In summary, these results show that FABP5 deficiency plays a significant role in locomotion activity, exploratory behavior, as well as social interaction. Furthermore, FABP7 deficiency is shown to play an important role in NMDA receptor expression, while FABP5 does not.

Vaporized nicotine in utero results in reduced birthweight, increased locomotion, and decreased voluntary exercise, dependent on sex and diet in offspring.

Rationale Clinical research has shown that prenatal exposure to nicotine may result in increased obesity risk later in life. Preclinical research has corroborated this finding, but few studies have investigated inhaled nicotine or the interaction with diet on obesity risk. Objective The aim of this study was to investigate the effects of prenatal nicotine exposure on both direct and indirect obesity measures, with both sex and diet as factors. Methods Pregnant rats were exposed to either vehicle or nicotine vapor (24 mg/mL or 59 mg/mL) throughout the entire gestational period. Offspring from each treatment group were given either a normal diet or a high fat diet starting at postnatal day 22. Caloric intake, body weight, spontaneous locomotion, sleep/wake activity, and voluntary exercise were measured throughout adolescence. Pregnancy weight gain and pup birthweights were collected to further measure developmental effects of prenatal nicotine exposure. Results Both maternal weight gain during pregnancy and pup weight at birth were decreased with prenatal nicotine exposure. Early adolescent males showed increased spontaneous activity in the open field following prenatal nicotine exposure compared to vehicle counterparts, particularly those given high-fat diet. Additionally, high dose nicotine prenatal treated males ran significantly less distance on the running wheel in late adolescence compared to vehicle counterparts, in the normal diet group only. Conclusion The results presented here show decreased birthweight, hyperactivity, and decreased voluntary exercise in adolescence following prenatal nicotine exposure in dose, sex, and diet dependent manners, which could lead to increased obesity risk in adulthood.

Summary Document Research on RDS Anti-addiction Modeling: Annotated Bibliography.

Annotated bibliography of genetic addiction risk severity (GARS) publications, pro-dopamine regulation in nutraceuticals (KB220 nutraceutical variants), and policy documents. Further research is required to encourage the field to consider "Reward Deficiency Syndrome (RDS) Anti-addiction Modeling" which involves early risk identification by means of genetic assessment similar to GARS, followed by induction of dopamine homeostasis by means of genetically guided pro-dopamine regulation similar to KB220. These results suggest that genetically based treatments may be a missing piece in the treatment of substance use disorder (SUD).

Addressing cortex dysregulation in youth through brain health check coaching and prophylactic brain development.

The Carter Center has estimated that the addiction crisis in the United States (US), if continues to worsen at the same rate, may cost the country approximately 16 trillion dollars by 2030. In recent years, the well-being of youth has been compromised by not only the coronavirus disease 2019 pandemic but also the alarming global opioid crisis, particularly in the US. Each year, deadly opioid drugs claim hundreds of thousands of lives, contributing to an ever-rising death toll. In addition, maternal usage of opioids and other drugs during pregnancy could compromise the neurodevelopment of children. A high rate of DNA polymorphic antecedents compounds the occurrence of epigenetic insults involving methylation of specific essential genes related to normal brain function. These genetic antecedent insults affect healthy DNA and mRNA transcription, leading to a loss of proteins required for normal brain development and function in youth. Myelination in the frontal cortex, a process known to extend until the late 20s, delays the development of proficient executive function and decision-making abilities. Understanding this delay in brain development, along with the presence of potential high-risk antecedent polymorphic variants or alleles and generational epigenetics, provides a clear rationale for embracing the Brain Research Commission's suggestion to mimic fitness programs with an adaptable brain health check (BHC). Implementing the BHC within the educational systems in the US and other countries could serve as an effective initiative for proactive therapies aimed at reducing juvenile mental health problems and eventually criminal activities, addiction, and other behaviors associated with reward deficiency syndrome.

Identification of stress-induced epigenetic methylation onto dopamine D2 gene and neurological and behavioral consequences.

The D2 dopamine receptor (DRD2) gene has garnered substantial attention as one of the most extensively studied genes across various neuropsychiatric disorders. Since its initial association with severe alcoholism in 1990, particularly through the identification of the DRD2 Taq A1 allele, numerous international investigations have been conducted to elucidate its role in different conditions. As of February 22, 2024, there are 5485 articles focusing on the DRD2 gene listed in PUBMED. There have been 120 meta-analyses with mixed results. In our opinion, the primary cause of negative reports regarding the association of various DRD2 gene polymorphisms is the inadequate screening of controls, not adequately eliminating many hidden reward deficiency syndrome behaviors. Moreover, pleiotropic effects of DRD2 variants have been identified in neuropsychologic, neurophysiologic, stress response, social stress defeat, maternal deprivation, and gambling disorder, with epigenetic DNA methylation and histone post-translational negative methylation identified as discussed in this article. There are 70 articles listed in PUBMED for DNA methylation and 20 articles listed for histone methylation as of October 19, 2022. For this commentary, we did not denote DNA and/or histone methylation; instead, we provided a brief summary based on behavioral effects. Based on the fact that Blum and Noble characterized the DRD2 Taq A1 allele as a generalized reward gene and not necessarily specific alcoholism, it now behooves the field to find ways to either use effector moieties to edit the neuroepigenetic insults or possibly harness the idea of potentially removing negative mRNA-reduced expression by inducing "dopamine homeostasis."

Selenoprotein P in a Rodent Model of Exercise; Theorizing Its Interaction with Brain Reward Dysregulation, Addictive Behavior, and Aging.

Exercise promotes health and wellness, including its operation as a protective factor against a variety of psychological, neurological, and chronic diseases. Selenium and its biomarker, selenoprotein P (SEPP1), have been implicated in health, including cancer prevention, neurological function, and dopamine signaling. SEPP1 blood serum levels were compared with a one-way ANOVA between sedentary (SED), moderately exercised (MOD) [10 m/min starting at 10 min, increasing to 60 min], and high-intensity interval training (HIIT) exercised rats [30 min in intervals of 2-min followed by a 1-min break, speed progressively increased from 10 to 21 m/min]. HIIT rats showed significantly higher serum SEPP1 concentrations compared to MOD and SED. More specifically, HIIT exercise showed an 84% increase in SEPP1 levels compared to sedentary controls. MOD rats had greater serum SEPP1 concentrations compared to SED, a 33% increase. The results indicated that increased exercise intensity increases SEPP1 levels. Exercise-induced increases in SEPP1 may indicate an adaptive response to the heightened oxidative stress. Previous studies found a significant increase in dopamine D2 receptor (D2R) binding in these same rats, suggesting a potential association between SEPP1 and dopamine signaling during exercise. Modulating antioxidants like SEPP1 through personalized therapies, including exercise, has broad implications for health, disease, and addiction.

Exercise Influences the Brain's Metabolic Response to Chronic Cocaine Exposure in Male Rats.

Cocaine use is associated with negative health outcomes: cocaine use disorders, speedballing, and overdose deaths. Currently, treatments for cocaine use disorders and overdose are non-existent when compared to opioid use disorders, and current standard cocaine use disorder treatments have high dropout and recidivism rates. Physical exercise has been shown to attenuate addiction behavior as well as modulate brain activity. This study examined the differential effects of chronic cocaine use between exercised and sedentary rats. The effects of exercise on brain glucose metabolism (BGluM) following chronic cocaine exposure were assessed using Positron Emission Tomography (PET) and [18F]-Fluorodeoxyglucose (FDG). Compared to sedentary animals, exercise decreased metabolism in the SIBF primary somatosensory cortex. Activation occurred in the amygdalopiriform and piriform cortex, trigeminothalamic tract, rhinal and perirhinal cortex, and visual cortex. BGluM changes may help ameliorate various aspects of cocaine abuse and reinstatement. Further investigation is needed into the underlying neuronal circuits involved in BGluM changes and their association with addiction behaviors.

Chronic Methylphenidate Effects on Brain Gene Expression: An Exploratory Review.

Methylphenidate (MP) is a psychostimulant commonly prescribed for individuals with attention deficit hyperactivity disorder (ADHD) but it is also taken with and without a prescription for performance enhancement. Prior research has characterized the effects of MP on behavior, cognition, and neurochemistry. This exploratory review covers the uses of MP and examined the effects of MP on gene expression in the brain following exposure. Overall, MP causes a wide-spread potentiation of genes, in a region-specific manner; consequently, inducing neuronal alterations, such as synaptic plasticity and transmission, resulting in observed behaviors and affects. Monoamine neurotransmitters and post-synaptic density protein genes generally had a potentiating effect in gene expression after exposure to MP.

Vaporized Δ9-THC in utero results in reduced birthweight, increased locomotion, and altered wake-cycle activity dependent on dose, sex, and diet in the offspring.

AIMS: Preclinical studies have found that chronic ∆9-tetrahydrocannabinol (THC) treatment is directly associated with weight gain when introduced during adolescence and adulthood, but the effect of prenatal THC is unclear. Clinical studies have demonstrated prenatal exposure to THC is a prospective predictor of increased health risks associated with obesity. Our study aims to examine prenatal THC impact on obesity risks in males and females throughout adolescence using a clinically relevant inhalation model. METHODS: Pregnant rats were exposed to one of the following from gestational day 2 through birth: 10 mg THC, 40 mg THC, or air. Daily 10-min inhalations were conducted in each animal from 0900 to 1200. Offspring from each treatment group were given either a high-fat diet (HFD) or a normal diet (ND). Food and bodyweights were collected daily, while circadian activity, locomotion, and exercise were measured periodically (PND 21-60). Pregnancy weight gain and birth weight were collected to determine early-life developmental effects. RESULTS: Rats prenatally treated with low-dose THC (LDTHC) generally had lower dark-cycle activity compared with control counterparts, but this altered activity was not observed at the higher dose of THC (HDTHC). In terms of open-field activity, THC doses displayed a general increase in locomotion. In addition, the LDTHC male rats in the ND showed significantly greater exploratory behavior. Prenatal THC had dose-dependent effects on maternal weight gain and birth weight. CONCLUSIONS: Overall, our findings indicate there are some activity-related and developmental effects of prenatal THC, which may be related to obesity risks later in life.

The Role of Estrogen Signaling and Exercise in Drug Abuse: A Review.

BACKGROUND: Discovering how sex differences impact the efficacy of exercise regimens used for treating drug addiction is becoming increasingly important. Estrogen is a hormone believed to explain a large portion of sex differences observed during drug addiction, and why certain exercise regimens are not equally effective between sexes in treatment. Addiction is currently a global hindrance to millions, many of whom are suffering under the influence of their brain's intrinsic reward system coupled with external environmental factors. Substance abuse disorders in the U.S. alone cost billions of dollars annually. REVIEW SUMMARY: Studies involving the manipulation of estrogen levels in female rodents, primarily via ovariectomy, highlight its impact regarding drug addiction. More specifically, female rodents with higher estrogen levels during the estrus phase increase cocaine consumption, whereas those in the non-estrus phase (low estrogen levels) decrease cocaine consumption. If estrogen is reintroduced, self-administration increases once again. Exercise has been proven to decrease relapse tendency, but its effect on estrogen levels is not fully understood. CONCLUSIONS: Such findings and results discussed in this review suggest that estrogen influences the susceptibility of females to relapse. Therefore, to improve drug-abuse-related treatment, exercise regimens for females should be generated based on key sex differences with respect to males.